N-substituted and n,n - disubstituted aminocarbonylalkyl compounds and their production

ABSTRACT

N-SUBSTITUTED AND N, N-DISUBSTITUTED AMINOCARBONYLALKYL COMPOUNDS OF THE FORMULA:   R2-N(-R3)-OC-A-N&lt;(-(R1-1,2-PHENYLENE)-Z-CO-)   WHEREIN Z IS SULFUR OR LOWER ALKYLAMINO, A IS LOWER ALKYLENE, R1 IS HYDROGEN, LOWER ALKYL, LOWER ALKOXY OR TRIFLUOROMETHYL R2 IS HYDROGEN, LOWER ALKYL OR HYDROXY (LOWER)ALKYL AND R3 IS HYDROGEN, LOWER ALKYL, HALO(LOWER) ALKYL, HYDRONY(LOWER)ALKYL, LOWER ALKOXY(LOWER)ALKYL, HYDROXY(LOWER)ALKOXY(LOWER)ALKYL, HYDROXYCARBONYL(LOWER)ALKYL, LOWER ALKOXYCARBONY(LOWER)ALKYL, PHENY BEARING OR NOT ONE OR MORE OF LOWER ALKYL, HALOGEN, HYDROXYL, LOWER ALKOXY AND LOWER ALKANOYL, PHENYL(LOWER)ALKYL HAVING OR NOT ON THE BENZENE RING ONE OR MORE OF LOWER ALKYL, HALOGEN, HYDROXYL, LOWER ALKOXY AND LOWER ALKANOLY, OR THE GROUP OF THE FORMULA:   -A&#39;&#39;-N(-R4)-R5   IN WHICH A&#39;&#39; IS LOWER ALKYLENE AND R4 AND R5 ARE EACH LOWER ALKYL OR PHENYL OR, WHEN TAKEN TOGETHER WITH THE ADJACENT NITROGEN ATOM, REPRESENTS A 5 TO 7-MEMBERED NITROGEN CONTAINING HETEROCYCLIC GROUP, OR THE GROUP OF THE FORMULA:   -N(-R2)-R3   MAY REPRESENT A 3 TO 7-MEMBERED HETROCYCLIC GROUP, PROVIDED THAT R1 IS NOT HYDROGEN WHEN R2 AND R3 ARE EACH LOWER ALKYL OR, IN THE LINKED FORM, REPRESENT A LOWER ALKYLENE GROUP OR AN OXA(LOWER)ALKYLENE GROUP AND R1 IS NOT CHLORINE WHEN BOTH R2 AND R3 ARE HYDROGEN. THESE COMPOUNDS EXHIBIT PHARMACOLOGICAL ACTIVITY SUCH AS ANTINFLAMMATORY ACTIVITY OR ANTIARRHYTHMIC ACTIVITY.

United States Patent O fice 3,661,921 Patented May 9, 1972 3,661,921N-SUBSTITUTED AND N,N DISUBSTITUTED AMINOCARBONYLALKYL COMPOUNDS ANDTHEIR PRODUCTION Suminori Umio, Kawanishi-shi, Japan, assignor toFujisawa Pharmaceutical Co., Ltd., Osaka-shi, Japan No Drawing.Continuation-impart of application Ser. No. 733,828, June 3, 1968. Thisapplication Apr. 1, 1969, Ser. No. 812,448

Claims priority, application Japan, June 5, 1967, 42/316,113; Sept. 30,1967, 42/62,872 Int. Cl. C07d 91/16, 49/34 11.5. Cl. 260-304 29 ClaimsABSTRACT OF THE DISCLOSURE N-substituted and N,N disubstitutedaminocarbonyl alkyl compounds of the formula:

A-CO-N wherein Z is sulfur or lower alkylamino, A is lower alkylene, Ris hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl, R ishydrogen, lower alkyl or hydroxy (lower)alkyl and R is hydrogen, loweralkyl, halo(lower) alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl,hydroxy(lower) alkoxy (lower) alkyl, hydroxycarbonyl (lower) alkyl,lower alkoxycarbonyl(lower)alkyl, phenyl bearing or not one or more oflower alkyl, halogen, hydroxyl, lower alkoxy and lower alkanoyl,phenyl(lower) alkyl having or not on the benzene ring one or more oflower alkyl, halogen, hydroxyl, lower alkoxy and lower alkanoyl, or thegroup of the formula:

in which A is lower alkylene and R and R are each lower alkyl or phenylor, when taken together with the adjacent nitrogen atom, represent a 5to 7-membered nitrogen containing heterocyclic group, or the group ofthe formula:

may represent a 3 to 7-membered heterocyclic group, provided that R isnot hydrogen when R and R are each lower alkyl or, in the linked form,represent a lower alkylene group or an oxa(lower)-alkylene group and Ris not chlorine when both R and R are hydrogen. These compounds exhibitpharmacological activity such as antiinfiammatory activity orantiarrhythmic activity.

This application is a continuation-in-part application of my copendingapplication Ser. No. 733,828, filed June 3, 1968 (now abandoned).

The present invention relates to N-substituted and N,N- disubstitutedaminocarbonylalkyl compounds having pharmacological activity such asantiinfiammatory activity and antiarrhythmic activity, and theirproduction.

The said N-substituted and N,N-disubstituted aminocarbonylalkylcompounds are representable by the formula:

R3 1 wherein Z is sulfur or lower alkylimino (e.g. methyl imino,ethylimino, etc.), A is lower alkylene (e.g. methylene, ethylene,methylmethylene, trimethylene, propylene, etc.), R is hydrogen, halogen(e.g. chlorine, bromine, iodine, etc.), lower alkyl (e.g. methyl, ethyl,propyl, isopropyl, butyl, etc.), lower alkoxy (e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy, etc.) or trifluoromethyl, R is hydrogen,lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, cyclohexyl,etc.) or hydroxy(lower)alkyl (e.g. hydroxymethyl, hydroxyethyl, etc.)and R is hydrogen, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl,butyl, cyclohexyl, etc.), halo(lower)alkyl (e.g. chloromethyl,chloroethyl, bromoethyl, etc.), hydroxy(lower) alkyl (e.g.hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, etc.), lowera1kanoy1oxy(lower)alkyl(e.g. acetyloxymethyl, propanoyloxyethyl), loweralkoxy(lower)alkyl (e.g. methoxyethyl, ethoxyethyl, methoxypropyl,etc.), hydroxy(lower) a1koxy(lower) alkyl (e.g. hydroxymethoxyethyl,hydroxyethoxyethyl, etc.), hydroxycarbonylflower) alkyl (e. g.hydroxycarbonylmethyl, hydroxycarbonylethyl, etc.), loweralkoxycarbonylflower)alkyl (e.g. methoxycarbonylmethyl,ethoxycarbonylmethyl, ethoxycarbonylethyl, etc.), phenyl hearing or notone or more of lower alkyl (e.g. methyl, ethyl, propyl, isopropyl,butyl, etc.), halogen (e.g. chlorine, bromine, iodine, etc.), hydroxyl,lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.)and lower alkanoyl (e.g. acetyl, propionyl, butyryl, etc.),phenyl(lower)alkyl (e.g. benzyl, phenethyl, etc.) having or not on thebenzene ring one or more of lower alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, etc.), halogen (e.g. chlorine, bromine, iodine, etc.),hydroxyl, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy,butoxy, etc.) and lower alkanoyl (e.g. acetyl, propionyl, butyryl,etc.), or the group of the formula:

in which A is lower alkylene (e.g. methylene, ethylene, methylmethylene,trimethylene, propylene, etc.) and R and R are each lower alkyl (e.g.methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, cyclohexyl,etc.) or phenyl or, when taken together with the adjacent nitrogen atom,represent a 5 to 7-membered heterocyclic group (e.g. l-pyrrolidinyl,piperidino, l-piperazinyl, 4-lower al kyl-l-piperazinyl,4-phenyl(lower)alkyl-l-piperazinyl, 4- hydroxy(lower)alkyl-l-piperazinyl, 4-phenyl-l-piperazinyl,4-(4-hydroxyphenyl)-1-piperazinyl, 4-(4chlorophenyl)-1-piperazinyl,morpholino, l-azepinyl, etc.), or the group of the formula:

may represent a 3 to 7-membered heterocyclic group (e.g. l-aziridinyl,l-diazepinyl, l-pyrrolidinyl, piperidino, 4-hydroxypiperidino,Z-hydroxyethylpiperidino, 4-hydroxyethylpiperidino, l-piperazinyl,4-hydr0Xy(lower)alkyl-1- piperazinyl, 4-lower or higheralkanoyloxy(lower)alkyl- 1- piperazinyl, 4-loweralkoxycarbonylflower)alkyl-l-piperazinyl, 4-loweralkanoyl(lower)alkyl-l-piperazinyl, 2,3,4, 5 or 6-mono, di ortri(lower)alkyl-l-piperazinyl such as 4-methyl-l-piperazinyl,4-ethyl-1-piperazinyl, 3-methyl-lpiperazinyl,2,5-dimethyl-l-piperazinyl, 3,4-dimethyl-l- 3-[4-phenyl-l-piperazinylcarbonyl (lower) alkyl] -2 3H) benzothiazolinone,

3- [4-phenyll-piperazinylcarbonyl (lower) alkyl] -4,5 ,6 or

7-ha1o-2 3H) -benzothiazolinone,

3- [4-phenyl (lower) alkyl-1-piperazinylcarbonyl(lower) alkyl] -4,5 ,6or 7-halo-2( 3 H) -benzthiazolinone,

3-[4-phenyl(lower)alkyl-l-piperazinylcarbonyl(lower) alkyl] -2( 3H -benzothiazolinone,

3 [4-phenyl (lower) alkyll-piperazinylcarbonyl (lower) alkyl]-4,5,6 or7-trifluoromethyl-2(3H)-benzothiazolinone,

1- [4-phenyl lower) alkyll-piperazinylcarbonyl (lower) alkyl]-3-loweralkyl4,5 ,6 or 7-trifluoromethyl-2-(1H)- benzothiazolinone,

3-[2,3,5 or 6-mono or di(lower)alkyl-4-hydroxy(lower)alkyll-piperazinylcarbonyl (lower alkyl] -2(3H) benzothiazolinone,

3-[2,3,5 or 6-mono or di(lower)alkyl-4-hydroxy(lower) alkyl-1-piperazinylcarbonyl( lower) alkyl] -4,5 ,6 or 7-halo-2 3H)-benzothiazolinone,

3-[2,3,5 or 6-mono or di(lower)alkyl-4-hydroxy(lower)alkyl-1-piperazinylcarbonyl(lower)alkyl]-4,5,6 or 7- trifluoromethyl-2 3H) -b enzothiazolinone,

3 -morpholinocarbonyl (lower) alkyl-2( 3H) -benzothiazolinone,

3-morpholinocarbonyl(lower)alkyl-4,5,6 or 7-halo-2(3H)-benzothiazolinone,

3-morpholinocarbonyl(lower)alkyl-4,5,6 or7-trifiuoromethyl-2(3H)-benzothiazolinone,

3- l-azepinylcarbonyl(lower) alkyl] -2 3H) -benzothiazolinone,

l-[l-azepinyl carbonyl(lower)alkyl]-3-lower alkyl-4,5,6

or 7-ha1o-2 1H) -benzimidazolinone,

N-[2,3,4,5 or 6-lower alky1phenyl(lower)alkyl]-2-oxo-3-benzothiazoline(lower) alkanoic amide, etc.

The designation lower indicates up to 4 carbon atoms.

It has now been found that the compounds [I] commonly andcharacteristically show antiinflammatory and/ or antiarrhythmicactivity. Among them, the following compounds exhibit relatively highantiinflammatory potency:

3- [4- (Z-hydroxyethyl) -1-piperazinylcarbonylmethyl] 5-chloro-2 (3 H)-benzothiazolinone,

N- (Z-hydroxypropyl -5 -chloro-2-oxo-3-beuzothiazolineacetamide,

N- (Z-hydroxyethyl) -6-chloro-2-oxo-3-benzothiazolineacetamide,

N- [2- (Z-hydroxyethoxy) ethyl]-5-chloro-2-oxo-3-benzothiazolineacetamide,

N- (2-hydroxypropyl -7-.chloro-2-oxo-3 -benzothiazolineacetanilide,

N- (Z-ethoxyethyl) -5-chloro-2-oxo-3 -benzo thiazolineacetamide,

N-methyl-S-trifiuoromethyl-2-oxo-3 -b enzothiazolineacetamide, etc.

Further, the following compounds exhibit relatively strongantiarrhythmic potency:

N- [2- (N,N-diethylamino) ethyl] -2-oxo-3-benzothiazolineacetamide,

N- [2- (N,N-diethylamino) ethyl]-5-chloro-2-oxo-3-benzothiazolineacetamide,

N- [3- (N,N-dimethylamino) propyl] -2-oxo-3-benzothiazolineacetamide,

N- [2- (N,N-diethylamino ethyl]-6-ethoxy-2-oxo-3-benzothiazolineacetamide, etc.

Accordingly, a basic object of the present invention is to embody theN-substitunted and N,N-disubstituted aminocarbonylalkyl compounds [I].Another object of this invention is to embody the pharmacologicallyactive compounds [I]. Another object of the invention is to embody thecompounds [I] useful as antiinflammatory agents. A further object of theinvention is to embody the compounds [I] useful as antiarrhythmicagents. A further object of the invention is to embody a process forwherein Z and 'R are each as defined above or the correspondingcarboxylalkyl compound of the formula:

COOH

wherein Z, A and R are each as defined above.

When the starting compound is the compound ['II], it is subjected toN-substituted or N,N-disubstituted aminocarbonylalkylation. TheN-substituted or N,N-disubstituted arninocarbonylalkylation may becarried out by reacting the compound [II] [J. Pharm. Soc., Japan, 77,347 (1957 or its reactive derivative with an alkyl halide of theformula:

[III] wherein X is halogen (e.g. chlorine, bromine, etc.) and A, R and Rare each as defined above. Examples of the reactive derivative of thecompound [II] are metal salts (e.g. sodium salt, potassium salt, calciumsalt, etc.). The reaction is usually eflected in an inert solvent (e.g.benzene, toluene, ether, methanol, ethanol, dimethylformamide, etc.). Inthe case using the compound [H] as such, it is desirable to use acondensing agent, of which examples are alkali hydroxide (e.g. sodiumhydroxide, potassium hydroxide, etc.), alkali carbonate (e.g. sodiumcarbonate, potassium carbonate, etc.), alkali alkoxide (e.g. sodiummethoxide, sodium ethoxide, potassium ethoxide, etc.), alkali hydride(e.g. sodium hydride, potassium hydride, etc.), alkali amide (e.g.sodium amide, potassium amide, lithium amide, etc.) and the like.

When the starting compound is the compound [III], it is subjected toN-substituted or N,N-disubstituted amination. The N-substituted orN,N-disubstituted amination may be carried out by reacting the compoundIII] [British Pat. 862,226], its salts or its reactive derivative withan amine of the formula:

wherein R and R are each as defined above. Examples of the salt of thecompound [III] are metal salts (e.g. sodium salt, potassium salt,calcium salt, etc.), ammonium salt, salts with organic base (e.g.triethylamine salt, etc.) and the like. Example of the reactivederivative of the compound [III] are acid halides (e.g. acid chloride,acid bromide, etc.), acid anhydrides (e.g. alkylphosphoric acidanhydride, dibenzylphosphoric acid anhydride, halophos phoric acidanhydride, dialkylphosphoric acid anhydride, sulfurous acid anhydride,thiosulfuric acid anhydride, sulfuric acid anhydride, alkylcarbonic acidanhydride, aliphatic carboxylic acid anhydride, aromatic carboxylic acidanhydride, symmetric acid anhydride, etc.), acid amides (e.g. acid amidewith imidazole, acid amide with 4-substituted imidazole, etc.), acidesters (e.g. methyl ester, ethyl ester, cyanomethyl ester, p-nitrophenylester, pentachlorophenyl ester, 2,4,5-trichlorophenyl ester, propargylester,

carboxymethyl thioester, pyranyl ester, methoxymethyl ester, phenylthioester, etc.) and acid azide. In the case using the compound III assuch, it is usually required to employ a condensing agent. Examples ofthe condensing agent are N,N'-dicyclohexylcarbodiimide,

N-cyclohexyl-N-morpholinoethylcarbodiimide,

N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,

N,N-diethyl-carbodiimide,

N,N'-diisopropylcarbodiimide,

N-ethyl-N-( 3 -dimethylaminopropyl) carbodiimide,

N,N'-carbonyldi 2-methylimidazole)pentamethyleneketene-N-cyclohexylimine,

diphenylketene-N-cyclohexylimine,

alkoxyacetylene,

1-alkoxy-l-chloroethylene,

tetraalkyl phosphite,

N-ethyl--phenylisoxazolium-3'-sulfonate,

ethyl polyphosphate,

isopropyl polyphosphate,

phosphorus oxychloride,

phosphorus trichloride,

thionyl chloride,

oxalyl chloride,

triphenyl phosphine, etc. i

The reaction is usually executed in an inert solvent (e.g. acetone,dioxane, acetonitrile, chloroform, ethylene dichloride, tetrahydrofuran,ethyl acetate, pyridine, etc.). 'If necessary, a basic substance (e.g.alkali carbonate, alkali hydrogen carbonate, trialkylamine, pyridine,etc.) may be present in the reaction.

Some of the compounds [I] may be alternatively produced from thoseprepared by either one of the said fundamental procedures (i.e.N-substituted or N,N-disubstituted aminocarbonylalkylation andN-substituted or N,N-disubstituted amination). An example of suchalternative procedures is shown in the following scheme:

wherein X is halogen (e.g. chlorine, bromine, etc.) and Z, A, R R and Rare each as defined above.

In the above scheme, the starting compound [Ia] is obtained by thereaction of the compound [III] with aziridine, which is an embodiment ofthe said N,N-disubstituted amination. The conversion of the compound[Ia] into the compound [Ib] may be executed by treat ment of the formerwith a hydrohalogenic acid (e.g. hydrochloric acid, hydrobromic acid,hydroiodic acid, etc.). This conversion, however, sometimes takes placesubsequent to the production of the compound [Ia] from the compound[III] when a hydrohalogenic acid is present. The compound [Ib] thusobtained can be reacted with an amine of the formula:

wherein R and R are each as defined above normally in the presence of abase (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate,sodium ethoxide, etc.) to give the compound [Ic], which may be alsoprepared directly from the compound [Ia] by reacting the same with thesaid amine.

Another example of the alternative procedures is shown in the followingscheme:

wherein X is halogen (e.g. chlorine, bromine, etc.) and Z, A, A, R R Rand R are each as defined above. In the above scheme, the startingcompound [Id] is obtained by the reaction of the compound [III] with anamine of the formula:

wherein A and -R are each as defined above, which is an embodiment ofthe said N-substituted or N,N-disubstituted amination. The conversion ofthe compound [Id] into the compound [Ie] may be eifected by halogenatingthe former with a halogenating agent in a per se conventional method.The subsequent conversion of the compound [Ie] into the compound [If]may be executed by reacting the former with an amine of the formula:

wherein R and R are each as defined above normally in the presence of abase (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate,sodium ethoxide, etc.).

Another example of the alternative procedures is shown in the followingscheme:

wherein R is hydrogen or lower alkyl (e.g. methyl, ethyl,

propyl, etc.), R and R are each hydrogen or lower alkyl (e.g. methyl,ethyl, propyl, etc.) and Z, A and R are each as defined above.

11 In the above scheme, the starting compound [Ig] is obtained by thereaction of the compound [III] with an amine of the formula:

wherein R' and R are each as defined above, which is an embodiment ofthe said -N,N-disubstituted amination. The conversion of the compound[Ig] into the compound [Ih] may be effected by reacting the former withan alkylene oxide of the formula:

wherein R is as defined above. The reaction can be effected in an inertsolvent (e.g. methanol, ethanol, acetone, chloroform, dioxane, benzene,n-hexane, toluene, xylene, etc.). In place of the inert solvent, thealkylene oxide (e.g. ethylene oxide, propylene oxide, etc.) itself maybe served as the reaction medium.

Another example of the alternative procedures is shown in the followingscheme:

wherein A" is lower alkylene (e.g. methylene, ethylene, methylmethylene,trimethylene, propylene, etc.) and Z, A, R R and R are each as definedabove. The above conversion of the compound [Ig] into the compound [Ii]may be carried out by reacting the former with a haloalkanol of theformula:

wherein X' is halogen (e.g. chlorine, bromine, iodine, etc.) and A" isas defined above. The reaction can be effected in an inert solvent (e.g.methanol, ethanol, ether, benzene, acetone, dimethylformamide,dimethylsulfoxide, etc.), if needed, in the presence of a condensingagent such as alkali carbonate (e.g. sodium carbonate, potassiumcarbonate, etc.), alkaline earth carbonate (e.g. magnesium carbonate,calcium carbonate, barium carbonate, etc.) or alkali hydrogen canbonate(e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.).Instead of the inert solvent, the haloalkanol (e.g. 2-bromoethanol,2-chloroethanol, 2 iodoethanol, 3 bromopropanol, 1- bromo 2 propanol,etc.) may be employed itself as the reaction medium.

Another example of the alternative procedures is shown in the followingscheme:

in which R R and R are each as defined above, A' is lower alkylene (e.g.methylene, ethylene, methylmethylene, trimethylene, propylene), R islower alkanoyl (e.g. acetyl, propionyl, butyryl) and Z, A and R are eachas defined above.

In the above scheme, the starting compound [Ij] is obtained by thereaction of the compound [II] with an alkyl halide of the formula:

wherein X, B, A and A' are each as defined above which is an embodimentof the said N-substituted or N,N-di substituted arninocarbonylalkylationor of the compound [III] with an amine of the formula:

wherein B and A' are each as defined above which is an embodiment of thesaid N-substituted or N,N-disubstituted amination. The one fallen in thecategory of the said compound [lb] or [Ii] may be also used as thestarting compound in this procedure. The conversion of the compound [Ij]into the compound [Ik] may be etfected by reacting the former with anacylating agent. Examples of the acylating agent are lower alkanoicanhydride (e.g, acetic anhydride, propionic anhydride, butyricanhydride) and lower alkanoyl halide (e.g. acetyl chloride, acetylbromide, propionyl chloride, butyryl chloride). The reaction can becarried out in a per se conventional procedure adopted for acylation.

A further example of the alternative procedures is shown in thefollowing scheme:

wherein R is lower alkyl (e.g. methyl, ethyl, propyl, isopropyl) and Z,B, A, A and R are each as defined above.

In the above scheme, the starting compound [Im] is obtained by thereaction of the compound [II] with an alkyl halide of the formula:

X-A-COB-A'-COR wherein X, B, A, A and R are each as defined above 1 3which is an embodiment of the said N-substituted or N,N- disubstitutedaminocarbonylalkylation or of the compound [III] with an amine of theformula:

wherein B, A' and R are each as defined above which is an embodiment ofthe said N-substituted or N,N-disubstituted amination. The conversion ofthe compound [Im] into the compound [In] may be effected by treating theformer with a reducing agent, preferably alkali metal hydride complex(e.g. lithium aluminium hydride) in an inert solvent (i.e. ether,tetrahydrofuran, dioxane).

A still further example of the alternative procedures is shown in thefollowing scheme:

wherein R is lower alkyl (e.g. methyl, ethyl, propyl, isopropyl) and Z,B, A, A" and R are each as defined above.

In the above scheme, the starting compound [I0] is obtained by thereaction of the compound [II] with an alkyl halide of the formula:

wherein X, B, A, A' and R are each as defined above which is anembodiment of the said N-substituted or N,N- disubstitutedaminocarbonylalkylation or of the compound [III] with an amine of theformula:

wherein B, A' and R are each as defined above which is an embodiment ofthe said N-substituted or N,N-disubstituted amination. The conversion ofthe compound [Io] into the compound [Ip] may be executed by treating theformer with a reducing agent, preferably alkali metal hydride complex(e.g. lithium aluminum hydride) in an inert solvent (e.g. ether,tetrahydrofuran, dioxane).

'As stated above, the compounds [I] are useful as antiinfiammatoryagents. Some of test results which ensure such utility are shown below.

(1) The inhibitory effect on swelling induced by Formalin, albumin orcarrageenin (a) The effect of3-[4-(2-hydroxyethyl)-1-piperazinylcarb0nylmethyl1-5 chloro 2(3H)benzothiazolinone.- Method: Wistar strain male rats each weighing 150 to200 g. were divided into two groups. One group rats) received orally 1ml. of a suspension of the test drug in 1% carboxymethylcellulosesolution per 100 g. of the body weight (the drug treated group); theother group (10 rats) received 1 ml. of 1% carboxymethylcellnlosesolution alone per 100 g. of the body weight in the similar fashion(control group). One hour after administration, formalin (2%, 0.1 ml.),egg white albumin (10%, 0.1 ml.) or carrageenin (1%, 0.1 ml.) was givento the animals into the hind paw to induce swelling. The paws thicknesswas measured by a slide caliper at varying time intervals afterinjection of the swelling-inducing substance. The swelling percent andthe inhibitory percent of swelling were calculated from the followingequations:

Swelling percent= w--W W W: Weight of the swelling-inducing substanceuninjected Inhibitory percent= X (p=reent) X 100 (percent) Swellingpercent= paw. w: Weight of the swelling-inducing substance injected paw.

Inhibitory percent 5 X 100 (percent) E: Swelling percent in controlgroup. F: Swelling percent in the drug treated group.

Results: The results are shown in the following tables:

TABLE 1 (Induced by Formalin) Inhibitory percent Dose (mg./ Cut- Testdrugs kg.) 1 hr. 2 hrs 3 hrs ting 3-[4-(2-hydroxyethyD-1-piper- 27.azinylcarbonylmethyl1-5- 27. chloro-2(3H)-benzothiazoli- 0. none.

Oxyphenylbutazone TABLE 2 (Induced by albumin) Inhibitory percent Dose-l Cut- Test drugs kg.) 1 hr. 2 hrs 3 hrs. ting3-[4-(2-hydroxyethyl)-1-piper- 500 48. 1 56. 2 59. 7 71. 8azhiylcarbonylmethyH-fi- 250 31. 4 34. 2 40. 6 51. 2chloro-2(3H)-benzothiazoli- 21.0 22. 3 25. 8 39. 7 none.

Oxyphenylbutazone 500 250 28. 6 125 4.7

TABLE 3 (Induced by carrageenin) Inhibitory percent Dose e! Cut- Testdrugs kg.) 1 hr. 2 hrs 3 hrs. 4 hrs. ting 3-[4-(2-hydroxyethyD-1- 60056. 3 57 7 55. 9 50. 0 67. 1 piperazinylcarbonyl- 250 43. 2 41 9 42. 340. 9 37. 0 methyl]-5-ehloro-2 125 39 0 7 9 16. 7 12. 2 13. 1(3H)-benzothiazolinone.

Oxyphenylbutazonm 500 250 47. 4 125 16. 6

N0'rE.In the group which received oxyphenylbutazone at a dose of 500 mg.lkgl.s, no reliable value could be obtained due to death of almost allamma (b) The effect of some other compounds [I] .--Method: The test wascarried out in the same manner as above.

Results: The results are shown in the following table:

TABLE 4 D Inhibitory percent (cutting) ose Test drugs (mg/kg.) FormalinAlbumin Carrageenin III CH3 CHaC ONHCHzCHOH CHaGONHOHaOH ICHgCONHCHzCHzO OH CH OH Cl 500 250 S 125 i r CH C ONHCHgCHzOH I C H: C ONH- O H S Cl- N l C HzCONHCHzCHzO CnHt CHzCONHCHa (2) The inhibitoryeffect of 3-[4-(2-hydroxyethyl)-1-piperazinylcar bonylmethyl] 5 chloro2(3H) benzothiazolinone on inflammatory exudate induced by formalin.

Method: Wistar strain male rats each weighing 150 to 200 g. were dividedinto two groups. One group (10 rats) received orally 1 ml. of asuspension of the test drug in 1% carboxymethylcellulose solution per100 g. of the body weight (the drug treated group); the other group (10rats) received 1 ml. of 1% carboxymethylcellulose solution alone per 100g. of the body weight in the similar fashion (control group). One hourafter administration, foramlin (5%, 1 ml.) was given intraperitoneallyto the animals to induce peritonitis. After hours, the amount of asciticfluid was measured. The rate of induced ascitic fluid and the inhibitorypercent of induced ascitic fluid were calculated from the followingequations:

t: Amount of ascitic fluid 20 hours after formalin being given.

Rate of induced ascitic fluid: X 100 (percent) inhibitory percent ofinduced ascitic fluid C X It 0 (percent) C: Rate of induced asciticfluid in control group. D: Rate of induced ascitic fluid in the drugtreated group.

Results: The results are shown in the following table:

TABLE 5 Dose Inhibitory Test drug (mg/kg.) percent344-(2hydroxyethyl)-1-piperazinylcar- 500 34. 7

bonylmcthyl]5-chloro-2(3H)-bcnzothi- 250 47. 2

azolinone. -0. 005

Oxyphcnylbutazone 500 NoTE.In the groups which receivedoxyphenylbutazone at a dose of 500 rug/kg. and of 250 mg./kg., nomeasurement was made due to death of almost all animals.

rabbit or guinea pig heart, which was suspended in tyrode T LE 6 ABsolution at 30 C. according to the Magnus method. A pair Test drug g g 12 3 4 5 of electrodes from a square-wave electronic stimulator wasinserted into the right atrial wall. A pulse of 0.5 milliiifiiiffiiiiiiliiitfii 228 g 2 5 8 8 second duration at a frequency of ZO/sec.was delivered e o e- (3 enz azo no 5 5 4 0 0 0 0 5 by the electrodes andthe voltage gradually increased until Phenylbumone 125 0 2 2 1 2 1 athreshold value for atrial fibrillation was determined.

Aqueous solutions of the drugs were added into the bath.

NOTE.-Of the group which received 500 mg./kg. of3-[4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl)-5-chloro2(3H)-benzothiazolinone,aThe efiects on threshqld Voltage for fibrlllatlon and on rat was deadfrom unknown cause. Of the group given 250 mg./kg., a rat heart ratewgre determ ed,

h h lbut e tw 3315551; 5: 2 d#3? 5, i12 iijifil s t tlfif} p my Mon oResults: The results are shown In the following tables:

TABLE 7 (0n rabbit heart) N-[2-(N,N-diethylamino)ethyll-Z-oxo-3-benzothiazw lineacetamide Qulnidine Procaine amideAverage change Average change Average change from the control from thecontrol from the control threshold threshold threshold Concentravoltagefor Inhibitory voltage for Inhibitory voltage for Inhibitory tion oftest atrial fibrillapercent of atrial fibrillapercent of atrialfibrillapercent of drug (g./ml.) tion, percent heart rate tron, percentheart rate tion, percent heart rate lXlO- 4 As clearly seen from theabove test results, the com- TABLE 8 (On guinea pig heart)N-[2-(N,N-dieyh Iamino)- ethyl]-2oxo-3-benzothiazolineacetamldeQuinidine Procaine amide Ajmalina Average change Averag ha g rage changeAverage change from the control from the control from the control frothe co t l threshold threshold threshold threshold voltage forInhibitory voltage for Inhibitory voltage for Inhibitory voltage [orInhibitory Concentration of atrial fibn'llapercent of atrialfibnllapercent of atrial fibrillapercent of atrial fibrillapercent oftest drug (g./ml.) tion, percent heart rate tion, percent heart ratetron, percent heart rate tion, percent heart rate pounds [I] arecharacterized by their potent antiinflam- (2) The efl ect on thearrhythmia induced by matory effect. Furthermore, the compounds [I] areleSS Lanatoside C in side efiects and may be safely applied to humanbelngs.

Some of the compounds [I] are also useful as anti- Method: The test drugwas administered to urethanearrhythrnic agents. Such utility areevidenced by the test aHeStPEtiZ-ed ellineapigs iI1 t1'aYe110l1S1Y or ly. After a results, some of which are shown below. g (1 m mmutesltlllltravenous injection 1 our in era a inistration e continuousinjection of (I) The efiectt 9 gffi sg Induced Lanatoside C into thejugular vein was started, such ina n a 1 jection causing arrhythmia at adose of about 600 ,ugJkg.

Method: During testing was carried out on the isolated and conductingcardiac arrest on further administration 19 unless the previousmedication was made. The effects of the test drug on the heart rate andLanatoside C induced arrhythmia and cardiac arrest were observed.

Results: The results are shown in the following tables:

20 the jugular vein of pentobarbital anesthetized dog, during whichelectric stimulation was given to the right auricle for 1 minute so thatatrial fibrillation was produced for several ten minutes or more. Theminimal eifective i.v.

TABLE 9 (ADMINISTRATION BY INTRAVENOUS ROUTE) Heart rate Lanatoside Og/kg) Before ad- After administraministra- Arrhythmia Cardiac ar- DoseNumber of tion (beats tion (inhibimean a: rest, mean (mg/kg.) animalsmin tory percent) S.E. l =I:S.E. 1

Control I 7 387=l=73 888i140 N-[Z-(N,N-diethylamino)ethyl1-2-0x0-3-benzo- 2 4 262 13 438:!zll5 98955259 thiazolineacetamide 5 5 267 17634=l=l55 920:1;80

10 8 258 14 719i171 987il88 Quinidiue 10 3 258 18 4283:1136 884il14 inmid 5 3 212 6 400*43 776:|:205 how 8 a e 10 4 252 17 4s0=b92 886:|:l78

Control I 5 256 404zk64 1, 199:l:l08

i 0. 5 250 0. 4 539il63 1, 0131279 Aimal ne 1. 0 5 262 4 618:l:302 1,0483;91

2. 0 5 263 3 4175:107 1 l55:l:304 5. 0 5 266 1. 5 448il32 1, 013=b34ll0. 0 5 276 8 579:l;236 1, 1353:456

B.E.= Standard error. I Physiological saline solution (0.5 ml.) wasgiven.

TABLE (Administration by oral route) Lanatoside C g/kg.)

Dose Cardiac (mgJ Number Arrhythmia, arrest, Test drug kg.) of animalsmean :hS.E. mean i313.

Control 1 3 4025:69 857=l=133 N -[2-(N,N-diethylarElno)e:1l;]l}y1]-l2-oxo- 3- enzo azo meacetamide 4 4 4l9=b37 l, 124il92 10 3 6061236 1,002=lz81 4 988 -209 1, 470=lz282 50 2 5483:2115 1, 350: -156 1 Distilledwater (2 ml.) was given.

(3) The prevention effect on the atrial fibrillation induced byacetylcholine Method: Acetylcholine was continuously injected into doseof the test drug was determined by observing the disappearance of 1 waveand the reappearance of p wave on the electrocardiogram.

Results: The results are shown in the following table:

(4) Toxicity The test drug was administered to mice intraperitoneally ororally at a variety of doses. The symptoms observed are shown in thefollowing table:

TABLE 12 Dose e-I e Administration Test drug routeN-[2-(N,N-diethylamino)ethyl1-2- oxo-3-benzothiazolineacetamide.

Intraperitonea1 Oral ing.

Quinidine IntrapcritoneaL.

Oral

Ptosis: Six deaths in 7 animals within 15 minutes.

Symptoms No special change.

Muscle relaxation; slight depression in movement activity; oppression inbreathing. Four deaths in 7 animals within 30 Muscle relaxation; slightto medial depression in corneal reflex.

Disturbance of gait; depression in grasping reflex; platycoria;oppression in breathminutes.

Slight to moderate muscle relaxation; ptosis.

Clear depression in consciousness, movement activity and graspingreflex. Moderate oppression in breathing; two deaths in 7 animals within24 to 48 hours. Four deaths in 7 animals within 30 minutes.

Moderate to strong ptosis.

Moderate to strong depression in consciousness and movement activity;muscle relaxation.

Procaine amide IntraperitoneaL.

Oral

.Ajmaline Intraperitoneah- Oral Disturgance of gait. Three deaths in 7animals within 30 minutes.

Ptosis. Clear depression in consciousness, movement activity andtonicity. Seven deaths in 7 animals within 30 minutes.

Ptosis. Clear deperession in consciousness, movement activity andtonicity.

Stronger depression in the above.

0. One death in 7 animals within 15 minutes.

Ptosis; muscle relaxation; one death in 7 animals within 15 minutes.Five deaths in 7 animals within 15 minutes.

Muscle relaxation; depression in movement activity.

Four deaths in 7 animals Within 15 minutes.

From the above test results, it can be seen that the toxicity of thecompounds [I] is considerably low for their marked arrhythimic potency.Therefore, the compounds [I] may be appliced to human beings with highsafety.

Accordingly, the compounds [I] are useful in treatment of inflammatoryconditions associated with pain, flare and/or swelling, which areprovoked by changes in cellular and vascular permeability, vasodilation,exudation of liquid constitution of the blood and of cellularconstitution, and/or proliferation of connective tissue cells andformation of granulation tissues. The compounds [I] are also useful intreatment of certain arrhythmias. Conversion of atrial fibrillation,abolition of paroxysmal atrial tachycardia, and management ofventricular ectopic beats represent typical examples of therapeuticamis.

The compounds [I] can be administered by the conventional methods, theconventional types of unit dosages or with the conventionalpharmaceutical carriers to produce an antiinflammatory or antiarrhythmiceffect in human beings and animals. Thus, they can be used in the formof pharmaceutical preparations, which contain them in admixture with apharmaceutical organic or inorganic carrier material suitable forenteral, parenteral or local applications. Oral administration by theuse of tablets, capsules or in liquid form such as suspensions,solutions or emulsions is particularly advantageous. When formed intotablets, the conventional binding and disintegrating agents used intherapeutic unit dosages can be employed. Illustrative of binding agentsthere can be mentioned glucose, lactose, gum acacia, gelatin, mannitol,starch paste, magnesium trisilicate and talc. Illustrative ofdisintegrating agents there can be mentioned corn starch, keratin,colloidal silica and potato starch. When administered as liquids theconventional liquid carriers can be used.

The unit dosage or therapeutically effective quantity of the compounds[I] for human beings for the therapeutic uses of the invention can varyover wide limits such as that of about 0.1 of a grain to about 25 grainsor more such as 50 grains. The upper limit is limited only by the degreeof effect desired and economic considerations. For oral administrationit is preferable to employ from about 1 to about 10 grains of thetherapeutic agent per unit dosage. It is indicated from animalexperiments that about 1 to about 10 grain dosages administered orallyfour times daily as needed will provide a preferred daily dosage. Ofcourse, the dosage of the particular therapeutic agent used can varyconsiderably, such as the age of the patient and the degree oftherapeutic effect desired. Each unit dosage form of the noveltherapeutic compounds can contain from about 5% to about 95% of thenovel therapeutic agents by weight of the entire composition with theremainder comprising conventional pharmaceutical carriers. By thetermpharmaceutical carrier it is intended toinclude non-therapeuticmaterials which are conventionally used with unit dosages and includesfillers, diluents, binders, lubricants, disintegrating agents andsolvents. Of course, it is possible to administer the noveltherapeutics, i.e. the pure compounds, without the use of apharmaceutical carrier.

Practical and presently-preferred embodiments of this invention areillustratively shown in the following examples.

EXAMPLE 1 (A) A mixture of 5-chloro-2(3H)-benzothiazolinone (5.0 g.),4'-hydroxy-2-chloroacetanilide (5.54 g.), potassium carbonate (3.75 g.)and acetone (20 ml.) is heated while refluxing for 6 hours. The reactionmixture is filtered while hot. The filtrate is concentrated to dryness.The residue is crystallized from ethyl acetate to give4-hydroxy-S-chloro-Z-oxo 3 benzothiazolineacetanilide (4.2 g.) ascrystals. M.P. 249 to 251 C.

(B) A mixture of 5-trifluoromethyl-2(3H)-benzothiazolinone (4.0 g.),4'-ethoxy-2-chloroacetanilide (4.01 g.), potassium carbonate (3.5 g.),sodium iodide (trace) and acetone ml.) is heated while refluxing for 6hours. After removal of the acetone by distillation, the residue isadmixed with water (200 ml.) and filtered. The collected crystals arerecrystallized from ethanol to give 4'-ethoxy-S-trifluoromethyl-2-oxo 3benzothiazolineacetanilide (3.4 g.) as crystals. M.P. 252 to 254 C.

Other examples of the compounds which can be prepared in the similarmanner include:

4'-acety1-5-chloro-2-oxo-3-benzothiazolineacetanilide (M.P. 282 to 283C.),

4-,5-dichloro,-2-oxo-3-benzothiazolineacetanilide (M.P. 241 to 242 C.),

5-trifluoromethyl-2-oxo-3-benzothiazolineacetamide (M.P. 227 to 229 C.),

2, '-dimethyl-5-chloro-2-oxo-3-benzothiazolineacetanilide (M.P. 284 C.),

3- [4- (2-hydroxyethyl l-piperazinylcarbonylmethyl] -5-chloro-2(3H)-benzothiazolinone (M.P. 159 to 161 C.),

3- (4-hydroxypiperizinocarbonylmethyl) -5-chloro-2 (3H)benzothiazolinone (M.P. 178 to 181 C.),

N- [2- (N,N-diethylamino ethyl] -2-oxo-3-benzothiazolineacetamide(maleate, M.P. 138.5 to 139.5 C.),

3-[4-(2-hydroxyethyl)-l-piperazinylcarbonylmethyl]-2(3H)-benzothiazolinone (maleate, M.P. 197 to 198 C.),

3-(4-methyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (M.P. 178 to 179 C.),3-morpholinocarbonylmethy1-5-chloro-2(3H)-benzothiazolinone (M.P. 199 to200 C.),3-(4-pheny1-l-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone(M.P. 188 to 190 C.),3-(4-methyl-1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)benzothiazolinone (M.P. 193 to 195 C.),

3- [4- Z-hydroxyethyl -1-piperazinylcarbonylmethyl]-5-trifiuoromethyl-2(3H)-benzothiazolinone M.P. 166 to 167.5 C.),

3- (4-methyl-1-homopiperazinyl/carbonylmethyl/)-5-chloro-2(3H)-benzothiazolinone (M.P. 136 to 137.5 C.),

N-(2-hydroxyethyl)-6-chloro-2-oxo-3-benzothiazo1ineacetamide (M.P. 222to 223 C.),

N-methyl-5-trifluoromethyl-2-oxo-3-benzothiazo1inacetamide (M.P. 223 to224 C.),

5-chloro-2-oxobenzothiazolin-3-ylacetylglycine ethyl ester (M.P. 194.5to 195.5 C.),

5-chloro-2-oxobenzothiazolin-3-ylacetylglycine (M.P. 246 to 247 C.),3-(4-acetylmethy1-1-piperazinylcarbonyl'methyl)-5-chloro-2(3H)-benzothiazolinone (M.P. 158 to 160 C.),

3- [2,5 -dimethyl-4- 2-propinyl)l-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone M.P. 145to 146 C.),

3- [2,5 -dirnethyl-4-(l-ethoxycarbonylmethyl)-1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone(M.P. 131 to 138 C.),

3- [2,5 -dimethyl-4- 2-hydroxyethyll-piperazinylcarbonylmethyl]-5-chloro 2(3H)-benzothiazolinone (M.P. 139to 141 C.),

3-(4-benzoyl-1-piperazinylcarbonylmethyl)-5-trifluoromethyl-3(2H)-benzothiazolinone (M.P. 183 to 184 C.),

3-[ [4- (Z-hydroxyethyl)-l-piperazinylcarbonyl]-1-ethyl]-5-chloro-benzothiazolinone (M.P. 8 to 92 C.),

1- [4- Z-hydroxyethyl) -1-piperazinylcarbonylmethyl]-3methyl-6-chloro-2(3H)-benzimidazolinone M.P. 172 to 174 C.),

1- [4-(2-hydroxyethyl) -1-piperazinylcarbonylmethyl] -3-methy1-5-chloro-2(3H)-benzimidazolinone (M.P. 171 to 173 C.),

l- [4- Z-hydroxypropyl) l-piperazinylc arbo nylmethyl]3-mcthyl-6-chloro-2 3H) -benzoimidazolinone (M.P. 202 to 206 C.),

3- [4-(2-hydroxypropyl) -1-piperazinylcarbonylmethyl] 5-chloro-2 (3H)-benzothiazolinone (M.P. 104 to 105 C.),

3- [4- Z-hydroxyethyl l-piperazinylcarbonylmethyl] -6-ethoxy-2(3H)-benzothiazolinone (M.P. 154 to 155 C.), etc.

EXAMPLE 2 (A) A mixture of ethyl 2-oxo-3-benzothiazoline-acetate (1.2g.), 2-(N,N-diethylamino)ethylamine (1.0 g.) and anhydrous ethanol (1.0g.) is heated while refluxing for 48 hours. After removal of the ethanolby distillation, the residue is extracted with dilute hydrochloric acid.The extract is made alkaline with 10% sodium hydroxide solution andshaken with chloroform. The chloroform layer is washed with water, driedand concentrated. The residue is crystallized from ethanol to giveN-[2-(N,N-diethylamino)ethyl]-2-oxo-3-benzothiazolineacetamide (2.0 g.)as colorless scales. M.P. 138.5 to 139.5 C. This base is treated withmaleic acid in a conventional manner to afford the maleate. M.P. 125 to128 C.

(B) A solution of ethyl 2-oxo-3-benzothiazolineacetate (600 mg.) inexcess of 1-(2-hydroxyethyl)piperazine is heated at 100 C. for about 20hours. After cooling, a large amount of water is added thereto, and theresulting mixture is extracted with chloroform. The chloroform extractis washed with water and shaken with 10% hydrochloric acid. Thehydrochloric acid layer is washed with ether, made alkaline with 20%sodium hydroxide solution and extracted with chloroform. The chloroformextract is washed with water, dried and concentrated. The residue iscrystallized from ethanol to give 3-[4-(2-hydroxyethyl) 1piperazinylcarbonylmethyl] 2(3H)- benzothiazolinone as crystals. M.P.197 to 198 C. (maleate).

(C) A mixture of ethyl 5 trifiuoromethyl 2 oxo-3- benzothiazolineacetate(1.5 g.) and morpholine (6.0 g.) is heated at 110 C. for hours whilestirring. After cooling, the reaction mixture is combined withchloroform and washed with water, dilute hydrochloric acid and water inorder. The chloroform solution is dried over magnesium sulfate andconcentrated. The residue is crystallized from ethanol to give3-morpholinocarbonylmethy1-5-trifiuoromethyl-2(3H)-benzothiazolinone(0.65 g.) as white needles. M.P. 188 to 190 C.

(D) A solution of ethyl 5-chloro-2-oxo-3-benzo-thiazolineacetate (4.0g.) in 1-(2-hydroxyethyl)piperazine is heated at 100 C. for 24 hours.After cooling, the resulting mixture is extracted with chloroform. Thechloroform extract is washed with Water and shaken with 10% hydrochloricacid. The hydrochloric acid layer is washed with chloroform, madealkaline with 10% sodium hydroxide solution and extracted withchloroform. The chloroform extract is washed with water, dried overmagnesium sulfate and concentrated. The residual oil (5.5 g.) is allowedto stand to form crystals, which are recrystallized from a mixture ofethyl acetate (40 ml.) and ethanol (15 ml.) to give3-[4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolin0ne(3.2 g.) as colorless crystals, M.P. 159 to 161 C.

Other examples of the compounds which can be prepared in the similarmanner include:

N-[2-(N,N-diethy1amino)-ethyl]-5-chloro-2-oxo-3-benzothiazolineacetamide(M.P. 127 to 128 C.; maleate, M.P. 119 to 121C.),

N-(2-morpholinoethyl)-2-oxo-3-benzothiazolineacetamide (M.P. 169 to 170C).

N- 3-( N,N-dimethylamino pro pyl -2-oxo-3-benzo thiazolineacetamide(maleate, M.P. 155 to 156 C.),

3- (4-methyl-1-piperazinylcarbonylmethyl )-5-chloro-2(3H)-benzothiazolinone (M.P. 178 to 179 C.),

3-(4phenyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (M.P. 179 to 180 C.),

3-morpholinocarbonylmethyl-S-chloro-Z(3H)-benzothiazolinone (M.P. 199 to200 C.),

N- 2- (N,N-diethylamino ethyl]-6-methyl-2-oxo-3-benzothiazolineacetamide (maleate, M.P. 113 to 114.5C.),

N- [2- (N,N-diethy1amino ethyl]-6-ethoxy-2-oxo-3-benzothiazolineacetamide (M.P. 131 C.),

3-(4-phenyl-1-piperazinylcarbonylmethyl)-5-trifiuoromethyl-2(3H)-benzothiazolinone(M.P. 188 to 190 C.),

3-(4-methyl-1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone(M.P. 193 to 185 C.),

3-[4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl]-5-trifluoromethyl-2(3H)-benzothiazo1inone (M.P. 166 to 167.5 C.),

3- [4- (Z-hydroxyethyl)-1-piperazinylcarbonylmethyl]-4-chloro-2(3H)-benzothiazolinone (M.P. 189 to 191 C.),

3- [4- (2-hydroxyethy1) -1-piperazinylcarbonylmethyl] -6-chloro-2(3H)-benzothiazolinone (M.P. 171 to 173 C.),

3- (4-methyll-diazepinyl -5-chloro-2 3H -benzothiazoninone (M.P. 136 to137.5 C.),

1- [4-(2-hydroxyethyl) -1-piperazinylcarbonylmethyl]-3-methyl-5-chloro-2(3H)-benzimidazolinone (M.P. 171 to 173 C.),

3- 4hydroxypiperidinocarbonylmethyl-5-trifiuoromethyl-2-(3H)-benzothiazolinone (M.P. 197 to 199 C.),

3- [4- 2-hydroxyethyl) -1-piperazinylcarbonylmethyl] -4- chloro2(3H)-benzothiazolinone (M.P. 189 to 191 C.),

4-hydroxy-5-chloro-2-oxo-3-benzothiazolineacetanilide (M.P. 249 to 251C.),

5 -trifluoromethyl-2-oxo-3-benzothiazolineacetamide (M.P. 227 to 229C.),

N-(2-hydroxyethyl)-6-chloro-2-oxo-3-benzothiazolineacetamide (M.P. 222to 223 C.),

3- l-piperazinyl carbonyl-methyl-5-chloro-2 (3H) -benzothiazolinone(M.P. 211 to 212 C.),

3- [4- (2-hydroxypropyl) l-pip erazinylcarbonyl'methyl] -5-chloro-2(3H)-benzothiazolinone (M.P. 104110 C.),

3 (4-acetylmethy1-1-piperazirrylcarbonyl-methyl) -5- chloro-2(3H)-benzothiazolinone (M.P. 158 to C.),

3-[2,5-dimethyl-4-(2-propinyl)-l-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone(M.P. 145 to 146 C.),

3- [4-(3-hydroxypropyl)-1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone (M.P. 118 to 120 C.),

3-(2,4,S-trirnethyl-l-piperazinylcarbonylmethyl)-5-chl0ro-2(3H)-benzothiazolinone (M.P. 167 to 173 C.),

3- 4-benzyl- 1 -piperazinylcarbonylmethyl) -5-chloro-2(3H)-benzothiazoline (M.P. 152 to 154 C.),

3-(4-benzyl-1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone(M.P. 183 to 184 C.),

3- [4-(2-hydroxyethyl) -1-piperazinylcarbonylmethyl] -7-chloro-2(3H)-benzothiazolinone (M.P. to 172 C.),

3-[ [4- (2-hydroxyethyl) -1-piperazinyl-carbonylmethyl]-1-ethyl]-5-ch1oro-2(3H)-benzothiazo1inone (M.P. 89 to 92 C.),

N- [2- [N-methyl-N- (Z-hydroxyethyl amino [ethyl] -5-chloro-2-oxo-3-benzothiazolinacetamide (M.P. 120 to 122 C.),

N-(Z-hydroxypropyl)-6-chloro-2-oxo-3-benzothiazolinacetamide (M.P. 169to 173 C.),

3 -[4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl]-6- 25ethoxy-2(3H)-benzothiazo1inone (M.P. 154 to 155 C.), etc.

EXAMPLE 3 (A) A mixture of 6-chloro-2-oxo-3-benzothiazolineacetic acid(5.04 g.) and thionyl chloride (50 ml.) is heated While refluxing for 2hours, and the thionyl chloride is distilled off. Thus obtained6-chloro-2-oxo-3-benzothiazolineacetyl chloride is dissolved in amixture of benzene (60 ml.) and chloroform (30 ml.), and the resultantsolution is dropwise added to a mixture of benzene (12 ml.),Z-aminoethanol (3.4 g.), water (5.6 ml.) and sodium carbonate (1.4 g.)cooled with ice-water while stirring. The resulting mixture is stirredat room temperature for 40 minutes and, after addition of water (70ml.), for several minutes. The precipitate is collected by filtration,Washed with water and recrystallized from a mixture of ethanol andchloroform to give N-(Z-hydroxyethyl)-6-chloro-2-oxo 3benzothiazolineacetamide (2.0 g.) as white cotton-like crystals, M.P.222 to 223 C.

(B) A mixture of -chloro- 2 oxo-3-benzothiazolineacetic acid (4.4 g.)and thionyl chloride is heated while refluxing for several hours, andthe thionyl chloride is distilled off. The obtained 5-chloro 2oxo-3-benzothiazolinylacetyl chloride is dissolved in benzene, and theresultant solution is dropwise added to a mixture of 2-(2-aminoethoxy)ethanol (4.0 g.), sodium carbonate (2.2 g.), water (12ml.) and benzene (40 ml.) cooled in an ice-water bath While stirring.The resulting mixture is stirred at room temperature for 3 hours and at60 C. for 30 minutes. After cooling, the separated crystals arecollected by filtration and recrystallized from water to give N [2 (2hydroxyethoxy)ethyl]-5-chloro-2-oxo-3- benzothiazolineacetarnide (3.6g.) as colorless scales. M.P. 133 to 134 C.

Other examples of the compounds which can be prepared in the similarmanner include:

N-methyl-5-trifiuoromethy1-2-oxo-3-benz0thiazolineacetamide (M.P. 223 to224 C.),

N,N-diethyl-5-chloro-2-oxo-3 benzothiazolineacetamide (M.P. 148 to 149C.),

N-(Z-hydroxypropyl)-7-chloro-2-oxo-3-benzothiazolineacetamide (M.P. 189to 191 C.),

N-(Z-hydroxypropyl)-5-chloro-2-oxo-3-benzothiazolineacetamide (M.P. 155to 156 C.),

N- (2-hydroxyethyl) -5-chloro-2-oxo-3 -benzothiazolineacetamide (M.P.223 to 224 C.),

N- 2-hydroxyethyl) -N-methyl-5 -chloro-2-oxo-3-b enzothiazolineacetamide(M.P. 115 to 117 C.),

3- l-piperazinyl carbonylmethyl-S-chloro-2 3H) -benzothiazolinone (M.P.211 to 212 C.),

5-chloro-2-oxobenzothiazolin-3-ylacetylglycine ethyl ester (M.P. 194.5to 195.5 C.),

5-chloro-2-oxobenzothiazolin-3-yl-acetyl-fl-alanine ethyl ester (M.P.150 to 151 C.)

S-chloro-2-oxobenzothiazo1in-3-ylacetylglycine (M.P.

246 to 247 C.),

5-ch1oro-2-oxobenzothiazolin-3-ylacetyl-/3-alanine (M.P.

187 to 189 C.),

3- [4- (Z-hydroxyethyl) 1-piperazinylcarbonylmethyl]6-chloro-2(3H)-beuzothiazolinone (M.P. 174 to 176 3- [4- 2-hy droxyethyl-1-piperazinylcarbonyl-methyl] -5- chloro-2(3H)-benzothiazolinone (M.P.159 to 161 3-(4-hydroxypiperizinocarbonylmethyl -5-chloro-2(3H)beuzothiazolinone (M.P. 178 to 181 C.),

N- [2- (N,N-diethylamino) -ethyl]-2-oxo-3-benzothiazo1ineacetamide (M.P.138.5 to 139.5 C.),

3- [4- Z-hydroxyethyl) -1-piperazinylcarbonylmethyl]2(3H)-benzothiazolinone (maleate, M.P. 197 to 1983-morpholinocarbonylmethyl-5-trifluoromethyl-2 3H beuzothiazolinone(M.P. 188 to 190 C.),

26 3-(4-methyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-beuzothiazolinone (M.P. 178 to 179 C.),3-(4-phenyl-1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone (M.P. 188 to 190 3-(4-methy1-1-hornopiperazinylcarbonylmethyl)-5-chloro-2-(3H)-benzothiazolone (M.P. 136 to 137.5 C.),

N- 2-ethoxyethyl) -5-chloro-2-oxo-3 -b enzothiazolineacetamide (M.P. 171to 173 C.),

3- [4- Z-hydroxypropyl -1-piperazinylcarbonylmethyl]- 5-chloro-2(3H)-benzothiazolinone (M.P. 104 to 1- [4- Z-hydroxyethyl)-1-piperazinylcarbonylmethyl]-3-methyl-S-chloro-Z(3H)-benzirnidazolinone (M.P. 171 to 173 C.),

1- [4- 2-hydroxyethyl) -1-piperazinylcarbonylmethyl] -3-methyl-6-chloro-2(3H)-benzoimidazolinone (M.P. 172 to 174 C.),

3- [4- (Z-hydroxypropyl -1piperazinylcarbonylmethyl]3-methyl-6-chloro-2(3H)-benzoimidazolinone (M.P. 202 to 206 C.),

3 -(4-acetylmethyl-1-piperazinylcarbonylmethyl) -5-chloro-2(3H)-benzothiazolinone (M.P. 158 to 160 3 [2,5 -dimethyl-4-2-propinyl) l-piperazinylcarb onylmethyl] -5-chloro-2 3H)-benzothiazolinone (M.P. to 146 C.),

3- [4- 3-hydroxypropyl 1-piperazinylcarbonylmethyl15-chloro-2(3H)beuzothiazolinone (M.P. 118 to 120 3- (2,4,5 -trimethyl-1-piperazinylcarbonylmethyl -5- chloro-2(3H) beuzothiazolinone (M.P. 167to 173 ')s 3- (4-benzyl-1-piperazinylcarbonylmethyl) -5-chloro-2(3H)-benzothiazolinone (M.P. 152 to 154 C.),

3-(4-benzyl-1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone(M.P. 183 to 184 C 7 3- [4-( 2-hydroxyethyl-1-piperazinylcarbonylmethyl] -7- chloro-2(3H)-benzothiazolinone (M.P.170 to 172 3-[ [4- (2-hydroxyethyl) l-piperazinylcarbonylmethyl]1-ethyl1-5-chloro-2(3H)-beuzothiazolinone (M.P.

89 to 92 C.),

N- [2- [N-methyl-N- (Z-hydroxyethyl amino] ethyl-5-chloro-2-oxo-3-benzothiazolinacetamide (M.P. 120 to 122 C.),

N-(2-hydroxypropyl)-6-chloro-2-oxo-3-benzothiazolinacetamide (M.P. 169to 173 C.),

3 [4- (Z-hydroxyethyl) -1-piperazinylcarbonylmethyl]-6-ethoxy-2(3H)-beuzothiazolinone (M.P. 154 to C.), etc.

EXAMPLE 4 (A) A mixture of 5 chloro-2-oxo-3-benzothiazolineacetic acid(5.0 g.) and thionyl chloride (50 ml.) is heated while refluxing for 2hours, and the thionyl chloride is distilled off. The thus obtained5-chloro-2-oxo-benzothiazolineacetyl chloride is dissolved in anhydrousbenzene (50 ml.), and the resultant solution is dropwise added to amixture of anhydrous benzene (100 ml.), aziridine (2.3 g.), potassiumcarbonate (5.03 g.) and water (15 ml.) cooled at 5 to 10 C. whilestirring. The resulting mixture is stirred at the same temperature for10 minutes. The reaction mixture is washed with 10% sodium carbonatesolution and water in order and dried over magnesium sulfate. Afterremoval of the solvent, the residue is crystallized from anhydrousbenzene to give 5-ch1oro- 3- l-aziridinylcarbonylmethyl -2 (3H)-benzothiazolinone (5.0 g.) as White granules. M.P. 137 to 139 C.

(B) 5 chloro-3-(l-aziridinyl)carbonylmethyl-2(3H)- beuzothiazolinone(5.2 g.) as above prepared is added to 99% ethanol (60 ml.), and theresulting mixture is heated while refluxing for 10 minutes. The reactionmixture is allowed to cool. The separated crystals are collected byfiltration to giveN-(Z-ethoxyethyl)--chloro-2-oxo-3-benzothiazolineacetarnide (3.2 g.) aswhite scales. M.P. 171 to 173 C.

(C) 5 chloro-3-(1-aziridinylcarbonylmethyl)-2(3H)- benzothiazolinone(0.7 g.) as above prepared is added to N,N-dicyclohexylamine (1.5 g.),and the resulting mixture is heated at 110 C. for 20 hours. The reactionmixture is allowed to cool. The separated crystals are collected byfiltration, washed with benzene and petroleum benzin in order andrecrystallized from ethanol to give N-[2(N,N-dicyclohexylamino)-ethyl]-5-chloro-2-oxo-3-benzothiazolineacetamide (0.5 g.) as white crystals. M.P. 209 to 210 C.

(D) A mixture of 5 chloro-2-oxo-3-benzothiazolineacetic acid (2.0 g.)and thionyl chloride (20 ml.) is heated while refluxing for 2 hours, andthe thionyl chloride is distilled off. The thus obtained 5chloro-2-oxo-3- benzothiazolineacetyl chloride is dissolved in anhydrousbenzene (20 ml.), and the resultant solution is dropwise added to amixture of aziridine (0.424 g.) and anhydrous benzene ml.) kept at 10 toC. while stirring. The resulting mixture is stirred at room temperaturefor 3 hours and allowed to stand overnight. After removal of thesolvent, the residue is dissolved in a mixture of water (50 ml.) and 10%sodium hydrogen carbonate solution (80 ml.), and the resulting solutionis stirred for several minutes. The separated crystals are collected byfiltration, washed with Water, dissolved in a mixture of ethanol (70ml.) and acetone ml.) and treated with active carbon. Then, the solutionis concentrated to about 60 ml. and allowed to stand overnight. Theseparated crystals are collected by filtration and recrystallized fromethanol to give N(2-chloroethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide (1.2 g.) aswhite crystals. M.P. 192 to 194 C.

(E) 2-oxo-3-benzothiazolineacetic acid is treated as above to giveN-(2-chloroethyl)-2-oxo-3-benzothiazoline acetamide. M.P. 159 to 162 C.

EXAMPLE 5 (A) N-(2-chloroethy1)-5-chloro-2-oxo 3benzothiazolineacetarnide (1.0 g.) and N-methylam'line (1.62 g.) arecharged in a steel bomb tube and heated at 90 C. for 5.5 hours. Then,10% hydrochloric acid and ethyl acetate are added thereto. The ethylacetate layer is extracted with 10% hydrochloric acid. The hydrochloricacid extract and the hydrochloric acid layer are combined together,washed with ethyl acetate and made alkaline with 10% sodium hydroxidesolution. The separated crystals are extracted with chloroform. Thechloroform extract is washed with water, dried over anhydrous magnesiumsulfate and concentrated. The oily residue is crystallized frompetroleum benzin and recrystallized from ethanol to give N- [2-(N-methylanilino ethyl] -5-chloro-2-oxo-3- benzothiazolineacetamide(0.45 g.) as white crystals. M.P. 155 to 157 C.

(B) N-(2-chloroethyl) 2 oxo 3 benzothiazolineacetamide (3.0 g.) andN-methylaniline (4.75 g.) are charged in a steel bomb tube and heated at110 C. for 5.5 hours. The reaction mixture is treated as above. Theobtained pale brown crystals (6.7 g.) are recrystallized from ethanol togive N-[2-(N-methylanilino)ethyl]-2- oxo-3-benzothiazolineacetamide (2.5g.) as White needles. M.P. 143 to 145 C.

EXAMPLE 6 To a solution of 3 (l-piperazinylcarbonylmethyl)-5-chloro-2-(3 H)-benzothiazolinone (0.45 g.) in methanol (30 ml.), thereis added propylene oxide (0.25 g.), and the resulting mixture is heatedat C. for 5 hours, during which propylene oxide (0.3 g.) is added twicethereto. The reaction mixture is concentrated under reduced pressure.The residual oil is crystallized from petroleum benzin andrecrystallized from a mixture of ethyl acetate and petroleum benzin togive 3-[4(2-hydroxypropyl)-lpiperazinylcarbonylmethyl] 5chloro-2(3H)-benzothiazolinone (0.43 g.) as colorless needles. M.P. 112to 115 C. Other examples of the compounds which can be prepared in thesimilar manner include:

3- [4- Z-hydroxyethyl -1-piperazinylcarbonylmethyl]5-chloro-2(3H)-benzothiazolinone (M.P. 159 to 161 C.),

3- [4- 2-hydroxyethyl l-piperazinylcarbonylmethyl] 6-chloro-2(3H)benzothiazolinone (M.P. 175 to 177 3- [4- (2-hydroxyethyl1-piperazinylcarbonylmethyl] 5-trifluoromethyl-2(3H)-benzothiazolinone(M.P. 166 to 167.5 C.),

3- [4-(2-hydroxyethyl) -1-piperazinylcarbonylmethyl]-4-chloro-2(3H)-benzothiazolinone (M.P.. 189 to 191 C.),

N- 2-hydroxyethyl) -6-chloro-2-oxo-3-benzothiazolinacetamide (M.P. 222to 223 C.),

N-(2-hydroxypropyl)-7-chloro-2-oxo-3-benzothiazolineacetamide (M.P. 189to 191 C.),

N-(2-hydroxypropyl)-5-chloro-2-oxo-3-benzothiazolineacetamide (M.P. 155to 156 C.),

N Z-hydroxyethyl -5-chloro-2-oxo-3-benzothiazolineacetamide (M.P. 223 to224 C.),

1-[4-(Z-hydroxyethyl)-1-piperazinylcarbonyl-3-methyl-6-chloro-2(3H)-benzirnidazolinone (M.P. 172 to 174 C.),

1- 4- 2-hydroxypropyl 1-piperazinylcarbonylmethyl]- 3-methyl-6-chloro-2(3H -benzoimidazolinone (M.P. 202 to 206 C.),

3- [4- 2-hydroxyethyl l-piperazinylcarbonylmethyl]6-ethoxy-2(3H)-benzothiazolir1one (M.P. 154 to 155 3- [4- Z-hydroxybutyll-piperazinylcarbonylmethyl]- 5-chloro-2(3H)-benzothiazolinone (M.P. 95to 98 C.), etc.

EXAMPLE 7 A mixture of 3 (1 piperazinyl)carbonylmethyl-S-chloro-2(3H)-benzothiazolinone (500* mg.), anhydrous potassium carbonate(400 mg), Z-hydroxyethyl bromide (300 mg.) and anhydrous ethanol (20ml.) is heated wh1le refluxing for 5 hours. The reaction mixture isconcentrated under reduced pressure. The residue is ex tracted withchloroform. The chloroform layer is dried over magnesium sulfate andconcentrated. The residue is crystallized from a mixture of ethylacetate and ethanol to give 3 [4 (2hydroxyethyl]-l-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone(370 mg.) as crystals. M.P. 159 to 160 C.

Other examples of the compounds which can be prepared in the similarmanner using 4,5,6 or 7-substituted or unsubstituted 3(l-piperazinyl)carbonyl(lower)-alkyl- 21(3H)-benzothiazolinone as thestarting compound inc ude:

3 [4-( l-ethoxycarbonylethyl l-piperazinylcarbonylmethyl] -5-chloro-2(3H -benzothiazolinone (maleate, M.P. 152 to 154 C.),

3- (4-acetylmethyl- 1-piperazinylcarbonylmethyl -5-2(3H)-benzothiazolinone (M.P. 158 to 160 C.),

3- [4- 3-hydroxypropyl 1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone (M.P. 118 to 120 3- 2,5-dimethyl-4-l-ethoxycarbonylmethyl)-1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone (M.P. 131 to138 C.),

3- [2,5-dimethyl-4- (2-propinyl)-1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone (M.P. to146 C.),

3- 2,5 -dimethyl-4-allyl- 1-pip erazinylcarbonyl-methyl)-5-chloro-2(3H)-benzothiazolinone (M.P. 136- to 1373-(2,4,5-trimethyl-1-piperazinylcarbonylmethyl)5-chloro-2(3H)-benzothiazolinone (M.P. 167 to 3- [2,5-dimethyl-4-(2-hydroxyethy1)-1-piperazinylcarbonylmethyl]--chloro-2(3H)-benzothiazolinone(M.P. 139 to 140 C.),

3 [4- (3 ',4'-dimethoxyphenethyll-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone (M.P. 189to 191 C.),

3-(4-acetylmethy1-1-piperazinylcarbonylmethyl)-5-trifiuoromethyl-2(3H)abenzothiazolinone (M.P. to 172 C.), etc.

EXAMPLE 8 To a mixture of3-[4-(Z-hydroxyethyl)-1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone(1.42 g.), potassium carbonate (1.4 g.) and chloroform (40 ml.), thereis dropwise added a mixture of acetyl chloride (0.8 g.) andtetrahydrofuran (5 ml.) while cooling in about 30 minutes. The resultantmixture is stirred at room temperature for 6 hours. The reaction mixtureis washed with water, dried and concentrated to give3-[4-(2-acetyloxyethyl) 1 piperazinylcarbonylmethyl] 5 chloro-2(3H)-benzothiazolinone as colorless oil. The oil is treated with maleicacid, and the resulting maleate is crystallized from ethanol to givecolorless scales. M.P. 199.5 to 200 C.

Other examples of the compounds which can be prepared in the similarmanner include:

3-[4- [2-isobutyryloxy-propyl]-1-piperazinylcarbonylmethyl] -5-chloro-2-3H) -benzothiazolinone (M.P. 123 to 125 C.),

3-[4-[Z-isobutyryloxy-ethyl]-1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone(M.P. 111 to 113 C.),

3- [4- (Z-acetyloxypropyl) l-piperazinylcarbonylmethyl] -5-chloro-2 3H)-benzothiazolinone (hydrochloride, M.P. 248 to 249 C.),

3- [4- 2-isobutyryloxyethyl) l-piperazinylcarbonylmethyl]-6-ethoxy-2(3H)-benzothiazolinone (M.P. 97 to 99 C.),

3 [4- (2-palmitoyloxyethyl)-1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone (M.P. 84to 86 C.),

3- [4- (2-palmitoy1oxypropyl-1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone (M.P. 94h to 95 C.),

3- [4- (Z-palmitoyloxyethyl) l-piperazinylcarbonylmethyl] -6-ethoxy-23H) -benzothiazolinone, etc.

EXAMPLE 9 To a solution of3-(4-acetylmethyl-l-piperazinylcarbonylmethyl)-5-chloro-2-(3H)benzothiazolinone (0.3 g.) in methanol ml.), there is added portionwisesodium borohydride (0.3 g.) at room temperature, and the resultantmixture is allowed to stand for 30 minutes After removal of the methanolfrom the reaction mixture by distillation, the residue is admixed withwater ml.), and the aqueous layer is extracted with ethyl acetate. Theextract is dried and concentrated. Petroleum benzene is added to theresidue so that oil is precipitated. The oil is collected bydecantation, solidified and crystallized from a mixture of ethyl acetateand petroleum benzene to give3-[4-(2-hydroxypropyl)-l-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone(0.2 g.) as colorless crystals, M.P. 104 to 105 C.

Other examples of the compounds which can be pre pared in the similarmanner include:

3-[4-(2-hydroxypropyl)-1-piperazinylcarbonylmethyl]-5-trifluoromethyl-2(3H)-benzothiazolinone (M.P. 152.5 to 154 C.),

1- [4- (2-hydroxypropyl) 1 -pip erazinylcarb onylmethyl]6-chloro-2(3H)-benzimidazolinone (M.P. 202 to 206 C.), etc.

30 EXAMPLE 10 (A) A mixture of ethyl 6-chloro-3-methyl-2-oxo-1-benzimidazolineacetate (0.5 g.) and 2-(N,N-diethylamino)-ethylamine (2.5g.) is heated at 110 C. for 20 hours. The reaction mixture is dissolvedin chloroform ml.) and washed with water. The chloroform layer isextracted with 10% hydrochloric acid. The hydrochloric acid layer iswashed with chloroform, made alkaline with 10% sodium hydroxide solutionand extracted with chloroform. The chloroform extract is Washed withwater, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue is washed with petroleum benzin andcrystallized from a mixture of benzene and petroleum benzin to giveN-[2-(N,N-diethylamino)ethyl] 6-chloro-3-methyl-2-oxo-l-benzimidazolineacetamide (0.2 g.) as white crystals M.P. 124 to126 C.

(B) A mixture of ethyl 5-chloro-3-methyl-2-oxo-1- benzimidazolineacetate(0.3 g.) and 1-(2-hydroxyethyl)- piperazine (1.0 ml.) is heated at C.for 15 hours. The reaction mixture is combined with ethyl acetate,washed with water and extracted with 10% hydrochloric acid. Thehydrochloric acid extract is washed with chloroform and made alkalinewith 10% sodium hydroxide solution while cooling with ice. The alkalinesolution is ex tracted with chloroform. The chloroform extract is driedover magnesium sulfate and concentrated under reduced pressure. Theresidue is crystallized from petroleum benzin and recrystallized fromethyl acetate to give 1- [4-(2-hydroxyethyl) 1piperazinylcarbonylmethyl]-5- chloro-3-methyl-2-oxobenzimidazoline (0.3g.) as colorless needles. M.P. 173 to 174 C.

Other examples of the compounds which can be prepared in the similarmanner include:

1-[4-(2-hydroxyethyl)-l-piperazinylcarbonylmethyl]- 3-methyl-6-chloro-23H) -benzimidazolinone (M.P. 172 to 174 C.),

1- [4- Z-hydroxypropyl) -1-piperazinylcarbonylmethyl]3-methyl-6-chloro-2(3H)-benzimidazolinone (M.P. 202 to 206 C.), etc.

EXAMPLE A A suitable formulation of tablets consists of:

Grams (1 N- [2- (N,N-diethylarnino) ethyl]-2-oxo-3-benzothiazolineacetamide 12.5 (2) Lactose 80 (3) Starch 5 (4)Magnesium stearate 2 The active ingredient, lactose and starch arethoroughly mixed and granulated. For tableting, the magnesium stearateis added, mixed with the granules, and the mixture tableted on a rotarypress. Use of this procedure The active ingredient, mannitol, starch andmagnesium stearate are thoroughly mixed and granulated. For tableting,the magnesium stearate is added, mixed with 31 granules, and the mixturetableted on a rotary press. Use of this procedure produces 100 tabletseach containing 50 mg. of the active ingredient.

EXAMPLE C A suitable formulation of drages consists of:

(1) 1 [4 (2 hydroxyethyl) 1 piperazinylcarbonylmethyl] chloro 2(3H)benzothiazolinone: 60,000 grams (2) Aerosil: 4,500 grams (3) Maizestarch: 4,500 grams (4) Stearic acid: 700 grams (5) Ethanol: 6.0 liters(6) Gelatin: 1,800 grams (7) Purified water: 20.0 liters (8) Talc: 600grams (9) Magnesium stearate: 375 grams From the above materials, thereare prepared 600,000 cores each containing 100 mg. of the activeingredient in a conventional manner.

EXAMPLE D A suitable formulation of suppositories consists of:

Grams (1) 1 [4 (2 hydroxyethyl) 1 piperazinylcarbonylmethyl] 5 chloro2(3H) benzothiazolinone 25,000 (2) Ethylenediaminetetraacetic aciddisodium salt dihydrate 900 (3) Witepsol H 12 124,100

From the above materials, there are prepared 100,000 supporitories eachcontaining 250 mg. of the active ingradient in a conventional manner.

What is claimed is:

1. A compound of the formula:

in which A is lower alkylene, R is lower alkyl, and R is lower alkyl,phenyl or hydroxyethyl.

2. A compound according to claim 1 in which Z is sulfur, R is hydrogenor halogen and R is halo(lower) alkyl.

3. A compound according to claim 1 in which Z is sulfur, R is halogenand R is hydroxy(lower)alkyl.

4. The compound according to claim 3 which is N-(2- hydroxyethyl) 5chloro 2 0X0 3 benzothiazolineacetamide.

5. The compound according to claim 3 which is N-(2- hydroxyethyl) 6chloro 2 oxo 3 benzothiazolineacetamide.

6. The compound according to claim 3 which is N-(2- hydroxypropyl) 5chloro 2 oxo 3 benzothiazolineacetamide.

7. The compound according to claim 3 which is N-(2- hydroxypropyl) 6chloro 2 0x0 3 benzothiazolineacetamide.

8. The compound according to claim 3 which is N-(2- hydroxypropyl) 7chloro 2 OX0 3 benzothiazolineacetamide.

9. A compound according to claim 1 in which Z is sulfur, R is halogenand R is lower alkoxy(lower)alkyl.

10. A compound according to claim 1 in which Z is sulfur, R is halogenand R is hydroxy(lower)alkoxy- (lower)alkyl.

11. The compound according to claim 10 which is N- [2-(2-hydroxyethoxy)ethyl] 5 chloro-2-oxo-3-benzo thiazolineacetamide.

12. A compound according to claim 1 in which Z is slllliflir, R ishaloogen and R is hydroxycarbonyl (ower) a y.

13. A compound according to claim 1 in which Z is sulfur, R is halogenand R is lower alkoxycarbonyl- (lower) alkyl.

14. A compound according to claim 1 in which Z is sulfur, R is halogenor trifiuoromethyl and R is phenyl or phenyl bearing one or twosubstituents selected from the group consisting of lower alkyl, halogen,hydroxy, lower alkoxy and lower alkanoyl.

15. A compound according to claim 1 in which Z is sulfur or loweralkylimino, R is hydrogen, halogen, lower alkyl or lower alkoxy and R isN,N-di(lower)alkylamino- (lower)alkyl.

16. A compound according to claim 15 in which Z is sulfur, and R ishydrogen.

17. The compound according to claim 16 which is N-[2 (N,Ndiethylamino)ethyl]-2-ox0-3-benzothiazo lineacetamide.

18. The compound according to claim 16 which is N-[3N,N-dimethylamino)propyl] 2 oxo-3-benzothiazolineacetamide.

19. A compound according to claim 15 in which Z is sulfur and R ishalogen.

20. The compound according to claim 10 which is N- [2 (N,Ndiethylamino)ethyl]5chloro-2-oXo-3-benzothiazolineacetamide.

21. A compound according to claim 15 in which Z is sulfur and R is loweralkyl.

22. The compound according to claim 21 which is N- [2 (N,Ndiethylamino)ethyl]-6-methyl-2-oxo-3-benzothiazolineacetamide.

23. A compound according to claim 15 in which Z is sulfur and R is loweralkoxy.

24. The compound according to claim 23 which is N- [2 (N,Ndiethylamino)ethyl]-6-ethoxy-2-oxo-3-benzothiazolineacetamide.

25. A compound according to claim 15 in which Z is lower alkylimino andR is halogen.

26. The compound according to claim 25 which is N- [2-(N,Ndiethylamino)ethyl] 3-methyl-6-chloro-2-oxo- 1-benzimidazolineacetamidc.

27. A compound according to claim 1 in which Z is sulfur, R is hydrogenor halogen and R is N-lower alkyl-N-phenylamino(lower)alkyl.

28. A compound according to claim 1 in which Z is sulfur, R is halogenand R is (N-lower alkyl-N-hydroxyethyl) amino (lower) alkyl.

29. The compound according to claim 28 which is N- [2 [N methyl-N-(2hydroxyethyl)amino]ethyl]-5- ch1oro-2-oXo-3-benzothiazolineacetamide.

34 References Cited UNITED STATES PATENTS 3,069,429 12/1962 Godson eta1. 260-304 5 ALEX MAZEL, Primary Examiner R. I. GALLAGHER, AssistantExaminer US. Cl. X.R.

10 260247.1, 247.2 A, 268 PL, 213.4 E, 294 A, 309.2,

